Dendritic cells in the skin were first found by Langerhans in 1868, and the function thereof as immunity-enhancing cells was reported by Cohn and Steinmann in 1973. In 1990s, dendritic cells were found to function as professional antigen presenting cells (APCs), and were found to play an important role in immune activation and regulation. Dendritic cells in the human body represent only about 0.3% of total circulating leukocytes, but consist of a heterogeneous population having a phenotype differentiated from that of macrophages. Dendritic cells are differentiated in that they are professional antigen-presenting cells, unlike B cells or macrophages displaying a relatively weak antigen-presenting capability. Dendritic cells have the ability to induce a primary immune response capable of stimulating naive T cells that have not been exposed to antigen, and these dendritic cells are the only cells having the capability to induce immunological memory. It is known that dendritic cells can function to induce strong immune responses, because these dendritic cells are antigen presenting cells (APCs) that express, on the cell surface, high levels of both antigen presenting MHC molecules (I/II) and co-stimulatory molecules, for example, CD-80 and CD-86, and adhesion molecules, for example, ICAM-1, and secrete various cytokines (IFN-alpha, IL-12, IL-18, etc.). It is known that, because dendritic cells express high levels of antigen presenting molecules (HMC molecules and co-stimulatory molecules) on the cell surface, and secrete various cytokines such as IFN-alpha, IL-12 and the like, these dendritic cells can induce the generation of antigen-specific killer T cells and the proliferation and activation of Th1 cells.
As described above, dendritic cells are the strongest antigen-presenting cells. A very small number of dentritic cells are present in vivo, but these cells strongly induce T cell immunity, and thus have been studied as therapeutic agents against cancers or infectious diseases in clinical studies focusing on the induction of immunity against the specific antigens. It was found that antigen immunogenicity was triggered by adoptive transfer of dendritic cells that were isolated from tissues or blood, antigen-pulsed, and matured in vitro. Thus, these dendritic cells are highly valuable as cellular vaccines for inducing antigen-specific immunity against cancer or pathogenic microbes (Inaba, K. et al., 3. Exp. Med., 178:479, 1993; Inaba, K. et al., Int. Rev Immunol., 6:197, 1990; Hsu, F. et al., Nature Med., 2:52, 1996). Techniques for the isolation and maturation of dendritic cells are described in a number of documents, and there are various methods, including a method comprising generating mature dendritic cells from immature dendritic cells derived from pluripotent cells having the capability to express any one of the characteristics of macrophages or dendritic cells, and bringing the immature dendritic cells into contact with dendritic cell maturation factors including IFN-α (European Patent No. 922,758); a method comprising culturing human CD34+ hematopoietic cells with (i) GM-CSF, (ii) TNF-α and IL-3 and/or (iii) GM-CSF and TNF-α to induce the formation of CD1a+ hematopoietic cells, and recovering the CD1a+ human dendritic cells from the culture (European Patent No. 663,930); and a method comprising isolating peripheral blood cells, enriching blood progenitor cells expressing CD34 antigen, and culturing the cells with a combination of hematopoietic growth factors and cytokines (WO 95/28479).
However, prior art documents and patents are merely directed to methods of generating dendritic cells by sensitizing immature dendritic cells with non-specific antigen, and do not teach a method of generating semi-mature dendritic cells by sensitizing immature dendritic cells with a specific selected self-antigen(autoantigen).
Accordingly, based on the function of antigen-specific semi-mature dendritic cells in immune-tolerance, the present inventors have found that semi-mature dendritic cells can be developed from immature dendritic cells pulsed with self-antigens selected among the overexpressed self-antigens in patients with rheumatoid arthritis. These semi-mature dendritic cells increase the expression of a specific gene and mediate immune tolerance to the selected self-antigens(autoantigen) and thus improve therapeutic efficacy on rheumatoid arthritis.